IGF2 mRNA binding protein-2 is a tumor promoter that drives cancer proliferation through its client mRNAs IGF2 and HMGA1
IGF2 mRNA binding protein-2 is a tumor promoter that drives cancer proliferation through its client mRNAs IGF2 and HMGA1
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DOI：
10.7554/elife.27155.001
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发表时间：
2017-07-28
期刊：
影响因子：
7.7
通讯作者：
Avruch, Joseph
中科院分区：
文献类型：
--
作者：
Dai, Ning;Ji, Fei;Avruch, Joseph
编码胰岛素样生长因子2 mRNA结合蛋白2/IMP2的基因在许多人类癌症中被扩增和过度表达，并伴有较差的预后。缺乏IMP2的小鼠在老年时表现出更长的寿命和更低的肿瘤负担。本研究表明，在多种人类癌细胞中，IMP2过表达可刺激癌细胞增殖，而消除IMP2可减少50-80%的癌细胞增殖。除了已知的促进胰岛素样生长因子2/IGF2丰度的能力外，我们发现IMP2通过结合和稳定编码DNA结合蛋白HMGA1（一种已知的致癌基因）的mRNA，强烈促进IGF的作用。HMGA1抑制IGF结合蛋白2/IGFBP2和Grb14的丰度，抑制IGF的作用。IMP2稳定HMGA1 mRNA和IMP2刺激IGF2的产生，协同驱动癌细胞增殖，解释了IMP2促进肿瘤的作用。IMP2促进增殖和IGF作用的能力需要mTOR磷酸化IMP2。
The gene encoding the Insulin-like Growth Factor 2 mRNA binding protein 2/IMP2 is amplified and overexpressed in many human cancers, accompanied by a poorer prognosis. Mice lacking IMP2 exhibit a longer lifespan and a reduced tumor burden at old age. Herein we show in a diverse array of human cancer cells that IMP2 overexpression stimulates and IMP2 elimination diminishes proliferation by 50-80%. In addition to its known ability to promote the abundance of Insulin-like Growth Factor 2/IGF2, we find that IMP2 strongly promotes IGF action, by binding and stabilizing the mRNA encoding the DNA binding protein HMGA1, a known oncogene. HMGA1 suppresses the abundance of IGF binding protein 2/IGFBP2 and Grb14, inhibitors of IGF action. IMP2 stabilization of HMGA1 mRNA plus IMP2 stimulated IGF2 production synergistically drive cancer cell proliferation and account for IMP2's tumor promoting action. IMP2's ability to promote proliferation and IGF action requires IMP2 phosphorylation by mTOR.